PIK3CA c.3073A>G, p.Thr1025Ala
NM_006218.4:c.3073A>G
COSMIC ID: COSM1041519
Pathogenic
The PIK3CA c.3073A>G (T1025A) variant demonstrates strong functional evidence of gain-of-function (PS3_Strong), is absent from population databases (PM2_Supporting), affects a critical functional domain (PM1_Supporting), and shows missense constraint (PP2_Supporting) along with reputable pathogenic reports (PP5_Supporting), leading to a final classification of Likely Pathogenic.
ACMG/AMP Criteria Applied
PS3
PM1
PM2
PP2
PP5
Genetic Information
Gene & Transcript Details
Gene
PIK3CA
Transcript
NM_006218.4
MANE Select
Total Exons
21
Strand
Forward (+)
Reference Sequence
NC_000003.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_006218.2 | Alternative | 21 exons | Forward |
| NM_006218.3 | Alternative | 21 exons | Forward |
Variant Details
HGVS Notation
NM_006218.4:c.3073A>G
Protein Change
T1025A
Location
Exon 21
(Exon 21 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 1025: T1025N, T1025S
Alternate Identifiers
COSM1041519
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.3073A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Likely Pathogenic
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
3 Path
2 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (2 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
16
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (16 mutations).
PM1 criterion applied.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 1025: T1025N, T1025S
PM5 criterion applied.
Functional Summary
The PIK3CA T1025A variant has been functionally characterized and demonstrated to be activating. Expression of this variant in Ba/F3 and MCF10A cell lines resulted in increased proliferation in the absence of growth factors, indicating a gain of function. This suggests a likely oncogenic effect.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.587
0.587
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Benign
PP3 Applied
No
Additional Predictors
Pathogenic:
mutationtaster: Dprovean: Dprimateai: Ddeogen2: D
Benign:
CADD: 4.22sift: Tpolyphen_prediction: benignmutationassessor: Lfathmm: Tmetasvm: Tmetalr: T
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi‐exon deletion) in a gene where loss-of-function is a known mechanism of disease." The evidence for this variant shows: it is a missense change (T1025A), not a null variant. Therefore, this criterion is not applied because the variant type does not meet the null variant requirement.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant irrespective of nucleotide change." The evidence for this variant shows: T1025A is novel and no other pathogenic missense at the same residue has been reported. Therefore, this criterion is not applied because there is no prior pathogenic variant causing the same amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled..." The evidence for this variant shows: no de novo or somatic mosaicism data are available. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Award PS3 if the functional assay meets the acceptability criteria delimited in (PMID: 31892348) with specifications added by the BMVCEP." The evidence for this variant shows: well-established in vitro functional studies in Ba/F3 and MCF10A cell lines demonstrate gain-of-function and increased proliferation without growth factors. Therefore, this criterion is applied at Strong strength because the assays meet VCEP quality metrics and demonstrate a damaging oncogenic effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls." The evidence for this variant shows: no case/control statistics or segregation points are available. Therefore, this criterion is not applied due to absence of case-level prevalence data.
PM1
PM1 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Supporting: Residues affecting critical functional domains provided in Table 4 for each gene." The evidence for this variant shows: residue T1025 lies within the kinase domain of PIK3CA, a critical functional region. Therefore, this criterion is applied at Supporting strength because the residue impacts a well-established functional domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent/rare from controls in an ethnically-matched cohort population sample (≥1)." The evidence for this variant shows: it is absent from gnomAD, 1000 Genomes, and ESP. Therefore, this criterion is applied at Supporting strength because the variant is not found in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: PIK3CA‐related disease is not a recessive condition and no in trans data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants." The evidence for this variant shows: it is a missense substitution, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate strength: novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen." The evidence for this variant shows: no other missense pathogenic variant at residue T1025 has been reported. Therefore, this criterion is not applied because the residue lacks prior pathogenic missense variation.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease." The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Supporting)
According to VCEP guidelines, the rule for PP2 is: "Supporting: Missense constraint computed in ExAC/gnomAD was utilized. Award PP2 if the z-score > 3.09." The evidence for this variant shows: PIK3CA has a missense z-score > 3.09, indicating constraint. Therefore, this criterion is applied at Supporting strength because PIK3CA is missense-constrained.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product." The evidence for this variant shows: the majority of in silico tools predict a benign effect and SpliceAI score is 0.05. Therefore, this criterion is not applied due to lack of consistent computational support for deleteriousness.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no phenotype/family history data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: ClinVar records 3 Pathogenic and 2 Likely Pathogenic submissions. Therefore, this criterion is applied at Supporting strength because of multiple reputable clinical laboratory reports.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes or ExAC." The evidence for this variant shows: allele frequency is 0% in population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a recessive (homozygous) disorder and heterozygotes are unaffected." The evidence for this variant shows: no homozygous or well-phenotyped heterozygous observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: functional studies demonstrate a damaging gain-of-function effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants are known to cause disease." The evidence for this variant shows: PIK3CA gain-of-function missense variants are well described in disease. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or in cis with a pathogenic variant." The evidence for this variant shows: no phasing data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: it is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Not applicable for any variant type except synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs." The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular diagnoses are reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Variant in reputable source reports as benign, but evidence not available." The evidence for this variant shows: no reputable benign reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no splice impact and non-conserved nucleotide." The evidence for this variant shows: it is a missense substitution, not synonymous. Therefore, this criterion is not applied.